Glucocorticoid receptor modulators to treat pancreatic cancer

ABSTRACT

Methods and compositions for treating a subject hosting a non-ACTH-secreting pancreatic tumor are disclosed. The methods include administering to the subject a chemotherapeutic agent and a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), to reduce the tumor load in the subject. The GRM may be a nonsteroidal GRM, and may be a nonsteroidal SGRM. The non-ACTH-secreting pancreatic tumor may be an exocrine pancreatic tumor. 
     The nonsteroidal SGRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure. Pharmaceutical compositions comprising a chemotherapeutic agent and a GRM are disclosed. The GRM in such pharmaceutical compositions may be a nonsteroidal GRM, and may be a SGRM, such as a nonsteroidal SGRM. The nonsteroidal SGRM may comprise: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to, and the benefit of, U.S.Provisional Patent Application No. 62/385,590, filed Sep. 9, 2016, whichapplication is hereby incorporated by reference herein in its entirety.

BACKGROUND

Pancreatic cancer is the fifth leading cause of cancer death in theUnited States. It is more common among men, and men between the ages of60 and 70 are most at risk. Pancreatic cancer usually begins in theducts of the pancreas when abnormal cells within the pancreas grow outof control and form a tumor. More than 95% of pancreatic cancers areclassified as exocrine pancreatic tumors. These tumors start in theexocrine cells that make pancreatic enzymes that help in digestion.Neuroendocrine pancreatic tumors account for less than 5% of allpancreatic tumors and they tend to grow slower than exocrine tumors.Pancreatic neuroendocrine tumors develop from the abnormal growth ofendocrine (hormone-producing) cells in the pancreas called islet cellsand thus are often referred to as “islet cell tumors.” Pancreatic canceroften has a poor prognosis, even when diagnosed early, and signs andsymptoms may not appear until the cancer is quite advanced and completesurgical removal is not possible.

Conventional treatment options for pancreatic cancer include surgery,radiation therapy (also termed “radiotherapy”) and chemotherapy. For thereasons stated above, only 15-25% of tumors are resectable at the timeof diagnosis and regrettably only 10-20% of patients resected willsurvive more than two years. Pancreatic tumors that are at an advancedstage often require radiotherapy or chemotherapy treatment.

Radiotherapy requires maximized exposure of the affected tissues whilesparing normal surrounding tissues. Interstitial therapy, where needlescontaining a radioactive source are embedded in the tumor, has become avaluable new approach. In this way, large doses of radiation can bedelivered locally while sparing the surrounding normal structures.Intraoperative radiotherapy, where the beam is placed directly onto thetumor during surgery while normal structures are moved safely away fromthe beam, is another specialized radiation technique. Again, thisachieves effective irradiation of the tumor while limiting exposure tosurrounding structures. Despite the obvious advantage of approachespredicated upon local control of the irradiation, patient survival rateis still very low.

Chemotherapy relies upon a generalized damage to DNA and destabilizationof chromosomal structure which eventually leads to destruction of cancercells. The non-selective nature of these treatments, however, oftenresults in severe and debilitating side effects. The systemic use ofthese drugs may result in damage to normally healthy organs and tissues,and compromise the long-term health of the patient.

The effects of glucocorticoid receptor (“GR”) mediated signaling pathwayon cancer cells in general are controversial. On one hand, it isbelieved that activating the GR signaling pathways advantageouslyinduces apoptosis in malignant lymphoid cancers (see Schlossmacher, J.Endocrinol. (2011) 211(1):17-25). On the other hand, it has beenreported that agents blocking the GR signaling pathway can potentiatechemotherapy in killing breast cancer cells (see U.S. Pat. No.9,149,485). It has been suggested that the combination ofneoplasia-treating agents and certain GR antagonists may be used fortreating over 30 types of neoplasia (cancer), including pancreaticcancer (Altschul et al., U.S. Pat. No. 8,658,128). It has also beensuggested that GR inhibitors can be used in combination with asomatostatin receptor-binding agent to treat an adrenocorticotropin(“ACTH”)-secreting, islet cell tumor of the pancreas (see WO2013/039916, Niemann et al., “Compositions for and Methods of Treatmentand Enhanced Detection of Non-Pituitary Tumors”). In terms of the effecton pancreatic cancer, however, the prevailing view is thatglucocorticoid, e.g., dexamethasone, can relieve side effects of thechemotherapeutic agent and should be co-administered withchemotherapeutic agents in treating pancreatic cancer (see Zhang et al.,BMC Cancer, 2006 Mar. 15 6: 61). Further, it has been reported thatdexamethasone inhibits pancreatic cancer cell growth. See, Norman etal., J. Surg. Res. 1994 July; 57(1): 33-8. The present application, incontrast to the prevailing view that activation of GR signaling benefitspancreatic cancer patients, provides a novel and surprising combinationtherapy that employs compounds that inhibit GR signaling to treatpatients suffering from certain types of pancreatic cancer.

BRIEF SUMMARY

Disclosed herein are novel methods for treating a subject hosting anon-ACTH-secreting pancreatic tumor. The methods comprise administeringto the subject an effective amount of a chemotherapeutic agent and aneffective amount of a GRM (where GRM is an acronym for “glucocorticoidreceptor modulator”) to reduce the tumor load of the non-ACTH-secretingpancreatic tumor in the subject. In preferred embodiments, the GRM is anonsteroidal GRM. The methods also comprise administering to the subjectan effective amount of a chemotherapeutic agent and an effective amountof a SGRM (where SGRM is an acronym for “selective glucocorticoidreceptor modulator”) to reduce the tumor load of the non-ACTH-secretingpancreatic tumor in the subject. In preferred embodiments, the SGRM is anonsteroidal SGRM. In some cases, the non-ACTH-secreting pancreatictumor is an exocrine pancreatic tumor.

In some cases, the chemotherapeutic agent is selected from the groupconsisting of antimicrotubule agents, alkylating agents, topoisomeraseinhibitors, endoplasmic reticulum stress inducing agents,antimetabolites, mitotic inhibitors and combinations thereof. In somecases, the chemotherapeutic agent is a taxane. In some cases, thechemotherapeutic agent is selected from the group consisting ofnab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin andcapecitabine.

In some cases, the GRM (e.g., a SGRM, such as a nonsteroidal SGRM) isorally administered. In some cases, the GRM is administered bytransdermal application, by a nebulized suspension, or by an aerosolspray.

In some cases, the effective amount of the GRM (e.g., a SGRM, such as anonsteroidal SGRM) is a daily dose of between 1 and 100 mg/kg/day,wherein the GRM is administered with at least one chemotherapeuticagent. In some embodiments, the daily dose of the GRM is 1, 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 30, 40, 50 60, 70, 80, 90 or 100 mg/kg/day. Insome cases, the GRM is administrated for at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, or 80 weeks.

In some cases, the GRM (e.g., a SGRM) is a nonsteroidal compoundcomprising a fused azadecalin structure. In some cases, the fusedazadecalin compound is a compound having the following formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; le is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.

In some cases, the fused azadecalin compound is

In some cases, the GRM (e.g., a SGRM) is a nonsteroidal compoundcomprising a heteroaryl ketone fused azadecalin structure or anoctahydro fused azadecalin structure. In some cases, the heteroarylketone fused azadecalin compound has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy,CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b),SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl groups are optionallysubstituted with 1-4 R^(2c) groups; alternatively, two R² groups linkedto the same carbon are combined to form an oxo group (═O);alternatively, two R² groups are combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinthe heterocycloalkyl ring is optionally substituted with from 1 to 3R^(2d) groups; R^(2a) and R^(2b) are each independently selected fromthe group consisting of hydrogen and C₁₋₆ alkyl; each R^(2c) isindependently selected from the group consisting of hydrogen, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, CN, and NR^(2a)R^(2b); eachR^(2d) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl, or two R^(2d) groups attached to the same ring atom arecombined to form (═O); R³ is selected from the group consisting ofphenyl and pyridyl, each optionally substituted with 1-4 R^(3a) groups;each R^(3a) is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₆ haloalkyl; and subscript n is an integerfrom 0 to 3; or salts and isomers thereof.

In some cases, the heteroaryl-ketone fused azadecalin compound has theformula:

In some cases, the octahydro fused azadecalin compound has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.

In some cases, the nonsteroidal SGRM is CORT125134, i.e.,(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

In some cases, the nonsteroidal SGRM is CORT125281, i.e.,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE shows tumor growth data from four (4) groups of mice thatwere treated with 1) vehicle, 2) paclitaxel at 7.5 mg/kg) (every fourdays, “Q4D”), 3) CORT125134 (30 mg/kg, dosed on day prior and same dayas paclitaxel) and paclitaxel (7.5 mg/kg, Q4D), or 4) CORT125281 (30mg/kg dosed on day prior to and same day as paclitaxel) and paclitaxel(7.5 mg/kg) (Q4D).

DETAILED DESCRIPTION A. Introduction

The methods disclosed herein can be used to treat a patient hosting anon-ACTH-secreting pancreatic tumor by administering an effective amountof a glucocorticoid receptor modulator (GRM), preferably a selectiveglucocorticoid receptor modulator (SGRM), in combination with aneffective amount of chemotherapy to reduce the tumor load of thepancreatic cancer. In preferred embodiments, the SGRM is a nonsteroidalSGRM. In embodiments, the nonsteroidal SGRM is a compound comprising afused azadecalin structure. In embodiments, the nonsteroidal SGRM is acompound comprising a heteroaryl ketone fused azadecalin structure, oran octahydro fused azadecalin structure. In view of the literaturereports that a GC, in combination with other agents, is the conventionaltreatment option for pancreatic cancer, using a SGRM in combination witha chemotherapeutic agent to reduce tumor load is surprising.

B. Definitions

As used herein, the term “tumor” and the term “cancer” are usedinterchangeably and both refer to an abnormal growth of tissue thatresults from excessive cell division. A tumor that invades thesurrounding tissue and/or can metastasize is referred to as “malignant.”A tumor that does not metastasize is referred to as “benign.”

As used herein, the term “subject” or “patient” refers to a human ornon-human organism. Thus, the methods and compositions described hereinare applicable to both human and veterinary disease. In certainembodiments, subjects are “patients,” i.e., living humans that arereceiving medical care for a disease or condition. This includes personswith no defined illness who are being investigated for signs ofpathology. Preferred are subjects who have an existing diagnosis of apancreatic cancer which is being targeted by the compositions andmethods of the present invention. In some cases, a subject may sufferfrom one or more types of cancer simultaneously, at least one of whichis a pancreatic cancer, which is targeted by the compositions andmethods of the present invention.

As used herein, the term “Adrenocorticotrophic Hormone” (ACTH) refers tothe peptide hormone produced by the anterior pituitary gland thatstimulates the adrenal cortex to secrete glucocorticoid hormones, whichhelp cells synthesize glucose, catabolize proteins, mobilize free fattyacids and inhibit inflammation in allergic responses. One suchglucocorticoid hormone is cortisol, which regulates metabolism ofcarbohydrate, fat, and protein metabolism.

As used herein, the term “non-ACTH-secreting pancreatic tumor” refers toa pancreatic tumor that is not an ACTH-secreting tumor. A“non-ACTH-secreting pancreatic tumor” does not secrete ACTH, or does notsecrete more than trace amounts of ACTH, and so does not cause increasedproduction and release of corticosteroids and cortisol from the adrenalcortex. An ACTH-secreting tumor is a non-pituitary tumor that secretesACTH thereby causing increased production and release of corticosteroidsand cortisol from the adrenal cortex. Exocrine pancreatic tumors, whichcounts for 95% of pancreatic tumors are believed to benon-ACTH-secreting pancreatic tumors. See,http://www.pancreaticcancer.org.uk/types. Some endocrine pancreatictumors (also called neuroendocrine tumors), e.g., an islet cell tumor ofthe pancreas, are ACTH secreting tumors. See Chertman et al., WordJournal of Medical and Surgical case reports Vol. (5), available atwww.npplweb.com/wjmscr/fulltext/2/13. Methods for determining whether atumor is a ACTH-secreting tumor are well known, including but are notlimited to those provided in this disclosure.

As used herein, the term “tumor load” or “tumor burden” generally refersto the number of cancer cells, the size of a tumor, or the amount ofcancer in the body in a subject at any given time. Tumor load can bedetected by e.g., measuring the expression of tumor specific geneticmarkers and measuring tumor size by a number of well-known, biochemicalor imaging methods disclosed herein, infra.

As used herein, the term “effective amount” or “therapeutic amount”refers to an amount of a pharmacological agent effective to treat,eliminate, or mitigate at least one symptom of the disease beingtreated. In some cases, “therapeutically effective amount” or “effectiveamount” can refer to an amount of a functional agent or of apharmaceutical composition useful for exhibiting a detectabletherapeutic or inhibitory effect. The effect can be detected by anyassay method known in the art. The effective amount can be an amounteffective to invoke an antitumor response. For the purpose of thisdisclosure, the effective amount of SGRM or the effective amount of achemotherapeutic agent is an amount that would reduce tumor load orbring about other desired beneficial clinical outcomes related to cancerimprovement when combined with a chemotherapeutic agent or SGRM,respectively.

As used herein, the terms “administer,” “administering,” “administered”or “administration” refer to providing a compound or a composition(e.g., one described herein), to a subject or patient.

As used herein, the term “combination therapy” refers to theadministration of at least two pharmaceutical agents to a subject totreat a disease. The two agents may be administered simultaneously, orsequentially in any order during the entire or portions of the treatmentperiod. The at least two agents may be administered following the sameor different dosing regimens. In some cases, one agent is administeredfollowing a scheduled regimen while the other agent is administeredintermittently. In some cases, both agents are administeredintermittently. In some embodiments, the one pharmaceutical agent, e.g.,a SGRM, is administered daily, and the other pharmaceutical agent, e.g.,a chemotherapeutic agent, is administered every two, three, or fourdays.

As used herein, the term “compound” is used to denote a molecular moietyof unique, identifiable chemical structure. A molecular moiety(“compound”) may exist in a free species form, in which it is notassociated with other molecules. A compound may also exist as part of alarger aggregate, in which it is associated with other molecule(s), butnevertheless retains its chemical identity. A solvate, in which themolecular moiety of defined chemical structure (“compound”) isassociated with a molecule(s) of a solvent, is an example of such anassociated form. A hydrate is a solvate in which the associated solventis water. The recitation of a “compound” refers to the molecular moietyitself (of the recited structure), regardless of whether it exists in afree form or an associated form.

As used herein, the term “pharmaceutically acceptable carrier” isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. Except insofar as any conventional media or agentis incompatible with the active compound, use thereof in thecompositions is contemplated. Supplementary active compounds can also beincorporated into the compositions.

The term “glucocorticosteroid” (“GC”) or “glucocorticoid” refers to asteroid hormone that binds to a glucocorticoid receptor.Glucocorticosteroids are typically characterized by having 21 carbonatoms, an α,β-unsaturated ketone in ring A, and an α-ketol groupattached to ring D. They differ in the extent of oxygenation orhydroxylation at C-11, C-17, and C-19; see Rawn, “Biosynthesis andTransport of Membrane Lipids and Formation of Cholesterol Derivatives,”in Biochemistry, Daisy et al. (eds.), 1989, pg. 567.

A mineralocorticoid receptor (MR), also known as a type I glucocorticoidreceptor (GR I), is activated by aldosterone in humans.

As used herein, the term “Glucocorticoid receptor” (“GR”) refers to afamily of intracellular receptors which specifically bind to cortisoland/or cortisol analogs. The glucocorticoid receptor is also referred toas the cortisol receptor. The term includes isoforms of GR, recombinantGR and mutated GR. “Glucocorticoid receptor” (“GR”) refers to the typeII GR which specifically binds to cortisol and/or cortisol analogs suchas dexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol. Oct.1, 2005 35 283-292).

“Glucocorticoid receptor modulator” (GRM) refers to any compound whichinhibits any biological response associated with the binding of GR to anagonist. For example, a GR agonist, such as dexamethasone, increases theactivity of tyrosine aminotransferase (TAT) in HepG2 cells (a humanliver hepatocellular carcinoma cell line; ECACC, UK). Accordingly, GRmodulators of the present invention can be identified by measuring theability of the compound to inhibit the effect of dexamethasone. TATactivity can be measured as outlined in the literature by A. Ali et al.,J. Med. Chem., 2004, 47, 2441-2452. A modulator is a compound with anIC₅₀ (half maximal inhibition concentration) of less than 10 micromolar.See Example 1, infra.

As used herein, the term “selective glucocorticoid receptor modulator”(SGRM) refers to any composition or compound which inhibits anybiological response associated with the binding of a GR to an agonist.By “selective,” the drug preferentially binds to the GR rather thanother nuclear receptors, such as the progesterone receptor (PR), themineralocorticoid receptor (MR) or the androgen receptor (AR). It ispreferred that the selective glucocorticoid receptor modulator bind GRwith an affinity that is 10× greater ( 1/10^(th) the K_(d) value) thanits affinity to the MR, AR, or PR, both the MR and PR, both the MR andAR, both the AR and PR, or to the MR, AR, and PR. In a more preferredembodiment, the selective glucocorticoid receptor modulator binds GRwith an affinity that is 100× greater ( 1/100^(th) the K_(d) value) thanits affinity to the MR, AR, or PR, both the MR and PR, both the MR andAR, both the AR and PR, or to the MR, AR, and PR. In another embodiment,the selective glucocorticoid receptor modulator binds GR with anaffinity that is 1000× greater ( 1/1000^(th) the K_(d) value) than itsaffinity to the MR, AR, or PR, both the MR and PR, both the MR and AR,both the AR and PR, or to the MR, AR, and PR.

As used herein, the terms “selective glucocorticoid receptor modulator”and “SGRM” do not include ORG 34517, or 11-(substitutedphenyl)-estra-4,9-diene derivatives, or 11-(substitutedphenyl)-estra-4,9-diene derivatives of the following formula:

wherein A is a residue of a 5- or 6-membered ring containing 2heteroatoms which are not connected to each other and independentlyselected from O and S, the ring being optionally substituted with one ormore halogen atoms, or A is a residue of a 5- or 6-membered ring whereinno double C—C bonds are present, containing 1 heteroatom selected from Oand S, which heteroatom is connected to the phenyl group at the positionindicated with an asterisk, the ring being optionally substituted withone or more halogen atoms; R1 is H or I-oxo(1-4C)alkyl; R2 is H,(1-8C)alkyl, halogen or CF3; X is selected from (H, OH), O, and NOH; andthe interrupted line represents an optional bond (see, e.g., claim 1 ofU.S. Pat. No. 8,658,128).

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients such as the said compounds,their tautomeric forms, their derivatives, their analogues, theirstereoisomers, their polymorphs, their deuterated species, theirpharmaceutically acceptable salts, esters, ethers, metabolites, mixturesof isomers, their pharmaceutically acceptable solvates andpharmaceutically acceptable compositions in specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to a pharmaceutical composition is intended to encompass aproduct comprising the active ingredient (s), and the inert ingredient(s) that make up the carrier, as well as any product which results,directly or indirectly, in combination, complexation or aggregation ofany two or more of the ingredients, or from dissociation of one or moreof the ingredients, or from other types of reactions or interactions ofone or more of the ingredients. Accordingly, the pharmaceuticalcompositions of the present invention are meant to encompass anycomposition made by admixing compounds of the present invention andtheir pharmaceutically acceptable carriers.

In some embodiments, the term “consisting essentially of” refers to acomposition in a formulation whose only active ingredient is theindicated active ingredient, however, other compounds may be includedwhich are for stabilizing, preserving, etc. the formulation, but are notinvolved directly in the therapeutic effect of the indicated activeingredient. In some embodiments, the term “consisting essentially of”can refer to compositions which contain the active ingredient andcomponents which facilitate the release of the active ingredient. Forexample, the composition can contain one or more components that provideextended release of the active ingredient over time to the subject. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

As used herein, the phrase “nonsteroidal backbone” in the context ofSGRMs refers to SGRMs that do not share structural homology to, or arenot modifications of, cortisol with its steroid backbone containingseventeen carbon atoms, bonded in four fused rings. Such compoundsinclude synthetic mimetics and analogs of proteins, including partiallypeptidic, pseudopeptidic and non-peptidic molecular entities.

Nonsteroidal SGRM compounds include SGRMs comprising a fused azadecalinstructure (which may also be termed a fused azadecalin backbone), SGRMscomprising a heteroaryl ketone fused azadecalin structure (which mayalso be termed a heteroaryl ketone fused azadecalin backbone), and SGRMscomprising an octahydro fused azadecalin structure (which may also betermed an octahydro fused azadecalin backbone). Exemplary nonsteroidalglucocorticoid receptor modulators comprising a fused azadecalinstructure include those described in U.S. Pat. Nos. 7,928,237 and8,461,172. Exemplary nonsteroidal glucocorticoid receptor modulatorscomprising a heteroaryl ketone fused azadecalin structure include thosedescribed in U.S. 2014/0038926. Exemplary nonsteroidal glucocorticoidreceptor modulators comprising an octahydro fused azadecalin structureinclude those described in U.S. Provisional Patent Appl. No. 61/908,333,entitled Octahydro Fused Azadecalin Glucocorticoid Receptor Modulators,filed on Nov. 25, 2013, and in U.S. patent application Ser. No.14/549,885, filed Nov. 21, 2014.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆, andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, and hexyl.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine, and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆, and include trifluoromethyl, fluoromethyl, etc.

The term “perfluoro” can be used to define a compound or radical whereall the hydrogens are replaced with fluorine. For example,perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, and perfluoroethoxy.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic, or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene, and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O, and S. Additionalheteroatoms can also be useful, including but not limited to, B, Al, Si,and P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14,15, or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, that has a methylene linking group. Somearyl groups have from 6 to 12 ring members, such as phenyl, naphthyl, orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic, fused bicyclic, or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O, or S. Additionalheteroatoms can also be useful, including but not limited to, B, Al, Si,and P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)—, and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5; or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2-, and 3-pyrrole; pyridine includes 2-,3- and 4-pyridine; imidazole includes 1-, 2-, 4- and 5-imidazole;pyrazole includes 1-, 3-, 4- and 5-pyrazole; triazole includes 1-, 4-and 5-triazole; tetrazole includes 1- and 5-tetrazole; pyrimidineincludes 2-, 4-, 5- and 6-pyrimidine; pyridazine includes 3- and4-pyridazine; 1,2,3-triazine includes 4- and 5-triazine; 1,2,4-triazineincludes 3-, 5- and 6-triazine; 1,3,5-triazine includes 2-triazine;thiophene includes 2- and 3-thiophene; furan includes 2- and 3-furan;thiazole includes 2-, 4- and 5-thiazole; isothiazole includes 3-, 4- and5-isothiazole; oxazole includes 2-, 4- and 5-oxazole; isoxazole includes3-, 4- and 5-isoxazole; indole includes 1-, 2- and 3-indole; isoindoleincludes 1- and 2-isoindole; quinoline includes 2-, 3- and 4-quinoline;isoquinoline includes 1-, 3- and 4-isoquinoline; quinazoline includes 2-and 4-quinoazoline; cinnoline includes 3- and 4-cinnoline;benzothiophene includes 2- and 3-benzothiophene; and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O, or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S, or N.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples ofpharmaceutically-acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid, and the like)salts, and quaternary ammonium (methyl iodide, ethyl iodide, and thelike) salts. It is understood that the pharmaceutically-acceptable saltsare non-toxic. Additional information on suitablepharmaceutically-acceptable salts can be found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, which is incorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to produce compounds which are notinherently unstable—and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions—such asaqueous, neutral, or physiological conditions.

“Pharmaceutically-acceptable excipient” and “pharmaceutically-acceptablecarrier” refer to a substance that aids the administration of an activeagent to—and absorption by—a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically-acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of ordinary skill in the art willrecognize that other pharmaceutical excipients are useful in the presentinvention.

C. Pancreatic Tumors

Pancreatic cancer is a malignant tumor within the pancreatic gland.Almost 90% of pancreatic cancer patients are older than 55. The averageage at the time this cancer is found is 72. Risk factors for pancreaticcancer include: age, male sex, African ethnicity, smoking, diets high inmeat, obesity, diabetes, chronic pancreatitis (has been linked, but isnot known to be causal), occupational exposure to certain pesticides,dyes, and chemicals related to gasoline, family history, Helicobacterpylori infection, gingivitis or periodontal disease. (Pancreatic Cancer.Von Hoff et al., ed., Maine; 2005.). Certain inherited genetic syndromescause as many as 10% of pancreatic cancers. Genetic markers that areassociated with pancreatic cancer include, e.g., mutations in the PNCA1,PALLD or BRCA2 gene (see, e.g., Banke et al., 2000, Med. Clin. North Am.84: 677-690; Meckler et al., 2001, Am. J. Surg. Path. 25: 1047-1053;Pogue-Geile et al., 2006, PLoS Med. 3: e516; Murphy et al., 2002, CancerRes. 62: 3789-3793). However, not all patients in the currentlyrecognized risk categories will develop pancreatic cancers. Manypancreatic cancers arise “sporadically” (i.e., in patients withoutfamily histories).

Early pancreatic cancer symptoms are non-specific and varied. Commonsymptoms include pain in the upper abdomen that typically radiates tothe back and is relieved by leaning forward (seen in carcinoma of thebody or tail of the pancreas), loss of appetite, nausea, vomitingsignificant weight loss and painless jaundice related to bile ductobstruction (carcinoma of the head of the pancreas). However, all ofthese symptoms can have multiple other causes and are not limited topancreatic cancer.

One or more of imaging based methods, such as, magnetic resonanceimaging (MRI), computed tomography (CT), X-ray, and positron emissiontomography (PET) scan, or ultrasonography (US), are often performed onsubjects suspected of having pancreatic cancer, e.g., based onexhibition of the related clinical symptoms. Results from these imagingtests are often combined with the patient's medical history, physicalexamination and lab tests to provide accurate diagnosis as well asinformation regarding the origin of the tumor.

The presence of pancreatic cancer, the type and stage of pancreaticcancer can be confirmed by histological analysis of the tumor performedby a pathologist. Histology dictates many aspects of pancreatic cancerclinical treatment, management, and prognosis.

There are two main types of pancreatic cancer based on whether the tumorstarts from the exocrine or endocrine gland of the pancreas. Tumorsformed from the exocrine gland of the pancreas are much more common.These exocrine pancreatic tumors count for about 95 percent ofpancreatic tumors. These tumors start in the exocrine cells that makepancreatic enzymes that help in digestion.

Pancreatic endocrine tumors constitute less than 5% of pancreatic tumorsand are ACTH-secreting tumors. These tumors are also referred to asislet cell tumors, and most are benign. A special type of tumor(ampullary tumor) of the endocrine pancreatic tumors can occur where thebile duct from the liver and the pancreatic duct empty into the smallintestine. Because this type of cancer often causes signs such asyellowing of the skin and eyes, it is usually found at an earlier stagethan most pancreatic cancers. The chances of successful treatment arebetter for patients suffering from ampullary cancer.

According to the American Joint Committee on Cancer (AJCC) criteria,pancreatic cancers can be at one of four stages: stage I through IV,with stage IV indicating that the cancer has spread and is more serious.Specifically, stage I pancreatic cancer includes tumors which have notspread into certain proscribed sensitive areas and which have noinvolved regional nodes or distal metastasis. Stage II includes tumorswhich have spread into the duodenum, bile duct, or “peripancreatic”tissues and which have no involved regional nodes or distal metastasis.Stage III cancer includes tumors which may have or may not have spreadinto these areas and which have involved regional nodes, but which showno evidence of distal metastasis. Stage IVA includes tumors which havespread into the stomach, spleen, large bowel or the adjacent largevessels and which have involved regional nodes, but show no evidence ofdistal metastasis. Stage IVB includes pancreatic tumors of any kind withnode status of any kind and with evidence of distal metastasis. Thoughreferred to, this pancreatic cancer staging system is rarely used in itspure form because the stages do not fully match patient prognosis ortreatment options. An alternative is the three stage classification(potentially resectable, locally advanced and metastatic), which isbased on radiological findings. Other prognosis factors are alsoconsidered. The grade of the cancer which indicates how abnormal thecells look under the microscope is sometimes listed on a scale from G1to G4, with G1 cancers looking the most like normal cells and having thebest outlook. For patients who have surgery, the extent of theresection, i.e., whether or not all of the tumor is removed, is alsoimportant with regard to outlook. This is sometimes listed on a scalefrom R0 to R2 with R0 indicating that all of tumor that can be seen hasbeen removed and R2 indicating that some tumor that can be seen cannotbe removed.

D. Non-Acth-Secreting Pancreatic Tumors

The methods disclosed herein are applicable for treatingnon-ACTH-secreting pancreatic tumors. After the diagnosis of pancreaticcancer, the tumor can be evaluated to determine the tumor origin, i.e.,whether the tumor is an exocrine or neuroendocrine tumor, byhistological analysis. In general, exocrine pancreatic tumors, whichcount for a majority of pancreatic tumors, are non-ACTH-secreting tumorsand thus encompassed within the scope of the claims. In general,neuroendocrine pancreatic tumors are ACTH secreting pancreatic tumorsand are not encompassed within the scope of the claims.

Alternatively, whether the tumor is a ACTH-secreting tumor can bedetermined by measuring the patients' ACTH level. This can be performedas an alternative or as an addition to the histological analysis. Thetypes of samples that are suitable for ACTH determination can be serum,plasma, saliva, urine, or any other biological fluid taken from asubject. The level of ACTH can be measured using various methods,including but not limited to, immunoassays, e.g., competitiveimmunoassay, radioimmunoassay, immunofluorometric enzyme assay, andELISA; competitive protein-binding assays; liquid chromatography (e.g.,HPLC); and mass spectrometry, e.g., high-performance liquidchromatography/triple quadrupole-mass spectrometry (LC-MS/MS).Commercial kits for measuring ACTH are readily available, e.g., fromMayo clinic (Test ID: ACTH), Siemens Healthcare Global (Immulite® 2000ACTH assay), and Roche Molecular Diagnostics (Catalog No. 03255751190).

The presence of an ACTH-secreting tumor in a patient is typicallyassociated with a blood ACTH level being significantly higher than thenormal reference value. Normal reference values vary depending on theassay method, type of sample, as well as the timing of sample collectionbecause, like cortisol, ACTH in healthy individuals varies during a24-hour period, reaching its highest level in the morning around 6-8 amand lowest at night around 11 pm. Various commercial kits provide thenormal reference values in their testing protocols. For example, thenormal range for ACTH using Mayo Clinc Test ID: ACTH is about 10-60pg/mL. If the pancreatic cancer patient has an ACTH level that issignificantly higher, e.g., at least 20%, 30%, 40%, 50%, 60%, 70% higherthan the upper limit of the normal range—generally indicating the tumoris an ACTH secreting tumor,—he or she is not a subject encompassed bythe claimed invention.

E. Glucocorticoid Receptor Modulators (GRM)

Generally, treatment of a non-ACTH-secreting pancreatic tumor can beprovided by administering an effective amount of a chemotherapeuticagent in combination with an effective amount of a glucocorticoidreceptor modulator (GRM) of any chemical structure or mechanism ofaction. In embodiments, the GRM is a selective GRM (SGRM). Inembodiments, treatment of a non-ACTH-secreting pancreatic tumor can beprovided by administering an effective amount of a chemotherapeuticagent in combination with an effective amount of a SGRM. In preferredembodiments, treatment of a non-ACTH-secreting pancreatic tumor can beprovided by administering an effective amount of a chemotherapeuticagent in combination with an effective amount of a nonsteroidal SGRM.Provided herein are classes of exemplary GRMs, and in particular,exemplary nonsteroidal SGRMs, and specific members of such classes.However, one of skill in the art will readily recognize other related orunrelated GRMs and SGRMs that can be employed in the treatment methodsdescribed herein.

Nonsteroidal Glucocorticoid Receptor Modulators

Provided herein are classes of exemplary nonsteroidal glucocorticoidreceptor modulators (nonsteroidal GRMs) and specific members of suchclasses that can be used for the method disclosed herein. However, oneof skill in the art will readily recognize other related or unrelatedglucocorticoid receptor modulators that can be employed in the treatmentmethods described herein. These include synthetic mimetics and analogsof proteins, including partially peptidic, pseudopeptidic andnon-peptidic molecular entities. For example, oligomeric peptidomimeticsuseful in the invention include (α-β-unsaturated) peptidosulfonamides,N-substituted glycine derivatives, oligo carbamates, oligo ureapeptidomimetics, hydrazinopeptides, oligosulfones and the like (See,e.g., Amour, Int. J. Pept. Protein Res. 43:297-304, 1994; de Bont,Bioorganic & Medicinal Chem. 4:667-672, 1996).

Examples of nonsteroidal GR modulators include the GR antagonistcompounds disclosed in U.S. Pat. Nos. 5,696,127; 6,570,020; and6,051,573; the GR antagonist compounds disclosed in US PatentApplication 20020077356, the glucocorticoid receptor antagonistsdisclosed in Bradley et al., J. Med. Chem. 45, 2417-2424 (2002), e.g.,4α(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 394531”) and4α(S)-benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 409069”); and the compounds disclosed in PCT InternationalApplication No. WO 96/19458, which describes nonsteroidal compoundswhich are high-affinity, highly selective antagonists for steroidreceptors, such as 6-substituted-1,2-dihydro-N-protected-quinolines.

For additional compounds that can be utilized in the methods of theinvention and methods of identifying and making such compounds, see U.S.Pat. No. 4,296,206 (see above); U.S. Pat. No. 4,386,085 (see above);U.S. Pat. Nos. 4,447,424; 4,477,445; 4,519,946; 4,540,686; 4,547,493;4,634,695; 4,634,696; 4,753,932; 4,774,236; 4,808,710; 4,814,327;4,829,060; 4,861,763; 4,912,097; 4,921,638; 4,943,566; 4,954,490;4,978,657; 5,006,518; 5,043,332; 5,064,822; 5,073,548; 5,089,488;5,089,635; 5,093,507; 5,095,010; 5,095,129; 5,132,299; 5,166,146;5,166,199; 5,173,405; 5,276,023; 5,380,839; 5,348,729; 5,426,102;5,439,913; and 5,616,458; and WO 96/19458, which describes nonsteroidalcompounds which are high-affinity, highly selective modulators(antagonists) for steroid receptors, such as 6-substituted-1,2-dihydroN-1 protected quinolines.

In some embodiments, the combination therapy for treating cancerinvolves a GRM comprising a fused azadecalin structure, a GRM comprisinga heteroaryl ketone fused azadecalin structure, or a GRM comprising anoctahydro fused azadecalin structure.

Exemplary GRMs comprising a fused azadecalin structure include thosedescribed in U.S. Pat. Nos. 7,928,237; and 8,461,172 and can be preparedas disclosed therein. These patents are incorporated herein in theirentirety. Such exemplary GRMs may be SGRMs. In some cases, the GRMcomprising a fused azadecalin structure has the following structure:

-   -   wherein    -   L¹ and L² are members independently selected from a bond and        unsubstituted alkylene;    -   R¹ is a member selected from unsubstituted alkyl, unsubstituted        heteroalkyl, unsubstituted heterocycloalkyl, —OR^(1A),        —NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), wherein    -   R^(1A) is a member selected from hydrogen, unsubstituted alkyl        and unsubstituted heteroalkyl,    -   R^(1C) and R^(1D) are members independently selected from        unsubstituted alkyl and unsubstituted heteroalkyl,    -   wherein R^(1C) and R^(1D) are optionally joined to form an        unsubstituted ring with the nitrogen to which they are attached,        wherein said ring optionally comprises an additional ring        nitrogen;    -   R² has the formula:

-   -   wherein    -   R^(2G) is a member selected from hydrogen, halogen,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃;    -   J is phenyl;    -   t is an integer from 0 to 5;    -   X is —S(O₂)—; and    -   R⁵ is phenyl optionally substituted with 1-5 R^(5A) groups,        wherein    -   R^(5A) is a member selected from hydrogen, halogen, —OR^(5A1),        —S(O₂)NR^(5A2)R^(5A3), —CN, and unsubstituted alkyl, wherein    -   R^(5A1) is a member selected from hydrogen and unsubstituted        alkyl, and    -   R^(5A2) and R^(5A3) are members independently selected from        hydrogen and unsubstituted alkyl,    -   or salts and isomers thereof.

Exemplary GRMs comprising a heteroaryl ketone fused azadecalin structureinclude those described in U.S. 2014/0038926, which can be prepared asdisclosed therein, and is incorporated herein in its entirety. Suchexemplary GRMs may be SGRMs. In some cases, the GRM comprising aheteroaryl ketone fused azadecalin structure has the followingstructure:

wherein

R¹ is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4heteroatoms each independently selected from the group consisting of N,O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a);

-   -   each R^(1a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, —CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl;    -   ring J is selected from the group consisting of a cycloalkyl        ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl        ring, wherein the heterocycloalkyl and heteroaryl rings have        from 5 to 6 ring members and from 1 to 4 heteroatoms each        independently selected from the group consisting of N, O and S;    -   each R² is independently selected from the group consisting of        hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b),        —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b), —SR^(2a),        —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl, wherein the heterocycloalkyl groups are        optionally substituted with 1-4 R^(2c) groups;    -   alternatively, two R² groups linked to the same carbon are        combined to form an oxo group (═O);    -   alternatively, two R² groups are combined to form a        heterocycloalkyl ring having from 5 to 6 ring members and from 1        to 3 heteroatoms each independently selected from the group        consisting of N, O and S, wherein the heterocycloalkyl ring is        optionally substituted with from 1 to 3 R^(2d) groups;    -   R^(2a) and R^(2b) are each independently selected from the group        consisting of hydrogen and C₁₋₆ alkyl;    -   each R^(2c) is independently selected from the group consisting        of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        —CN, and —NR^(2a)R^(2b);    -   each R^(2d) is independently selected from the group consisting        of hydrogen and C₁₋₆ alkyl, or two R^(2d) groups attached to the        same ring atom are combined to form (═O);    -   R³ is selected from the group consisting of phenyl and pyridyl,        each optionally substituted with 1-4 R^(1a) groups;    -   each R^(3a) is independently selected from the group consisting        of hydrogen, halogen, and C₁₋₆ haloalkyl; and    -   subscript n is an integer from 0 to 3;    -   or salts and isomers thereof.

Exemplary GRMs comprising an octahydro fused azadecalin structureinclude those described in U.S. Pat. Pub. No. 20150148341 filed on Nov.21, 2014 and can be prepared as described therein. The disclosure ofU.S. Pat. Pub. No. 20150148341 is incorporated herein in their entirety.Such exemplary GRMs may be SGRMs. In some cases, the GRM comprising anoctahydro fused azadecalin structure has the following structure:

wherein

-   -   R¹ is a heteroaryl ring having from 5 to 6 ring members and from        1 to 4 heteroatoms each independently selected from the group        consisting of N, O and S, optionally substituted with 1-4 groups        each independently selected from R^(1a);    -   each R^(1a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl;    -   ring J is selected from the group consisting of an aryl ring and        a heteroaryl ring having from 5 to 6 ring members and from 1 to        4 heteroatoms each independently selected from the group        consisting of N, O and S;    -   each R² is independently selected from the group consisting of        hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b),        —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b), —SR^(2a),        —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl having from 1 to 3 heteroatoms each        independently selected from the group consisting of N, O and S;    -   alternatively, two R² groups on adjacent ring atoms are combined        to form a heterocycloalkyl ring having from 5 to 6 ring members        and from 1 to 3 heteroatoms each independently selected from the        group consisting of N, O and S, wherein the heterocycloalkyl        ring is optionally substituted with from 1 to 3 R^(2c) groups;    -   R^(2a), R^(2b) and R^(2c) are each independently selected from        the group consisting of hydrogen and C₁₋₆ alkyl;    -   each R^(3a) is independently halogen; and    -   subscript n is an integer from 0 to 3;        or salts and isomers thereof.

F. Identifying Selective Glucocorticoid Receptor Modulators (SGRMs)

To determine whether a test compound is a SGRM, the compound is firstsubjected to assays to measure its ability to bind to the GR and inhibitGR-mediated activities, which determines whether the compound is aglucocorticoid receptor modulator. The compound, if confirmed to be aglucocorticoid receptor modulator, is then subjected to a selectivitytest to determine whether the compound can bind specifically to GR ascompared to non GR proteins, such as the estrogen receptor, theprogesterone receptor, the androgen receptor, or the mineralocorticoidreceptor. In one embodiment, a SGRM binds to GR at a substantiallyhigher affinity, e.g., at least 10 times higher affinity, than to non-GRproteins. A SGRM may exhibit a 100-fold, 1000-fold or greaterselectivity for binding to GR relative to binding to non GR proteins.

i. Binding

A test compounds' ability to bind to the glucocorticoid receptor can bemeasured using a variety of assays, for example, by screening for theability of the test compound to compete with a glucocorticoid receptorligand, such as dexamethasone, for binding to the glucocorticoidreceptor. Those of skill in the art will recognize that there are anumber of ways to perform such competitive binding assays. In someembodiments, the glucocorticoid receptor is pre-incubated with a labeledglucocorticoid receptor ligand and then contacted with a test compound.This type of competitive binding assay may also be referred to herein asa binding displacement assay. A decrease of the quantity of labeledligand bound to glucocorticoid receptor indicates that the test compoundbinds to the glucocorticoid receptor. In some cases, the labeled ligandis a fluorescently labeled compound (e.g., a fluorescently labeledsteroid or steroid analog). Alternatively, the binding of a testcompound to the glucocorticoid receptor can be measured directly with alabeled test compound. This latter type of assay is called a directbinding assay.

Both direct binding assays and competitive binding assays can be used ina variety of different formats. The formats may be similar to those usedin immunoassays and receptor binding assays. For a description ofdifferent formats for binding assays, including competitive bindingassays and direct binding assays, see Basic and Clinical Immunology 7thEdition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E. T.Maggio, ed., CRC Press, Boca Raton, Fla. (1980); and “Practice andTheory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B.V.Amsterdam (1985), each of which is incorporated herein by reference.

In solid phase competitive binding assays, for example, the samplecompound can compete with a labeled analyte for specific binding siteson a binding agent bound to a solid surface. In this type of format, thelabeled analyte can be a glucocorticoid receptor ligand and the bindingagent can be glucocorticoid receptor bound to a solid phase.Alternatively, the labeled analyte can be labeled glucocorticoidreceptor and the binding agent can be a solid phase glucocorticoidreceptor ligand. The concentration of labeled analyte bound to thecapture agent is inversely proportional to the ability of a testcompound to compete in the binding assay.

Alternatively, the competitive binding assay may be conducted in theliquid phase, and any of a variety of techniques known in the art may beused to separate the bound labeled protein from the unbound labeledprotein. For example, several procedures have been developed fordistinguishing between bound ligand and excess bound ligand or betweenbound test compound and the excess unbound test compound. These includeidentification of the bound complex by sedimentation in sucrosegradients, gel electrophoresis, or gel isoelectric focusing;precipitation of the receptor-ligand complex with protamine sulfate oradsorption on hydroxylapatite; and the removal of unbound compounds orligands by adsorption on dextran-coated charcoal (DCC) or binding toimmobilized antibody. Following separation, the amount of bound ligandor test compound is determined.

Alternatively, a homogenous binding assay may be performed in which aseparation step is not needed. For example, a label on theglucocorticoid receptor may be altered by the binding of theglucocorticoid receptor to its ligand or test compound. This alterationin the labeled glucocorticoid receptor results in a decrease or increasein the signal emitted by label, so that measurement of the label at theend of the binding assay allows for detection or quantitation of theglucocorticoid receptor in the bound state. A wide variety of labels maybe used. The component may be labeled by any one of several methods.Useful radioactive labels include those incorporating ³H, ¹²⁵I, ³⁵S,¹⁴C, or ³²P. Useful non-radioactive labels include those incorporatingfluorophores, chemiluminescent agents, phosphorescent agents,electrochemiluminescent agents, and the like. Fluorescent agents areespecially useful in analytical techniques that are used to detectshifts in protein structure such as fluorescence anisotropy and/orfluorescence polarization. The choice of label depends on sensitivityrequired, ease of conjugation with the compound, stability requirements,and available instrumentation. For a review of various labeling orsignal producing systems which may be used, see U.S. Pat. No. 4,391,904,which is incorporated herein by reference in its entirety for allpurposes. The label may be coupled directly or indirectly to the desiredcomponent of the assay according to methods well known in the art. Insome cases, a test compound is contacted with a GR in the presence of afluorescently labeled ligand (e.g., a steroid or steroid analog) with aknown affinity for the GR, and the quantity of bound and free labeledligand is estimated by measuring the fluorescence polarization of thelabeled ligand.

ii. Activity

1) HepG2 Tyrosine Aminotransferase (TAT) Assay

Compounds that have demonstrated the desired binding affinity to GR aretested for their activity in inhibiting GR mediated activities. Thecompounds are typically subject to a Tyrosine Aminotransferase Assay(TAT assay), which assesses the ability of a test compound to inhibitthe induction of tyrosine aminotransferase activity by dexamethasone.See Example 1. GR modulators that are suitable for the method disclosedherein have an IC₅₀ (half maximal inhibition concentration) of less than10 micromolar. Other assays, including but not limited to thosedescribed below, can also be deployed to confirm the GR modulationactivity of the compounds.

2) Cell-Based Assays

Cell-based assays which involve whole cells or cell fractions containingglucocorticoid receptors can also be used to assay for a test compound'sbinding or modulation of activity of the glucocorticoid receptor.Exemplary cell types that can be used according to the methods of theinvention include, e.g., any mammalian cells including leukocytes suchas neutrophils, monocytes, macrophages, eosinophils, basophils, mastcells, and lymphocytes, such as T cells and B cells, leukemia cells,Burkitt's lymphoma cells, tumor cells (including mouse mammary tumorvirus cells), endothelial cells, fibroblasts, cardiac cells, musclecells, breast tumor cells, ovarian cancer carcinomas, cervicalcarcinomas, glioblastomas, liver cells, kidney cells, and neuronalcells, as well as fungal cells, including yeast. Cells can be primarycells or tumor cells or other types of immortal cell lines. Of course,the glucocorticoid receptor can be expressed in cells that do notexpress an endogenous version of the glucocorticoid receptor.

In some cases, fragments of the glucocorticoid receptor, as well asprotein fusions, can be used for screening. When molecules that competefor binding with the glucocorticoid receptor ligands are desired, the GRfragments used are fragments capable of binding the ligands (e.g.,dexamethasone). Alternatively, any fragment of GR can be used as atarget to identify molecules that bind the glucocorticoid receptor.Glucocorticoid receptor fragments can include any fragment of, e.g., atleast 20, 30, 40, 50 amino acids up to a protein containing all but oneamino acid of glucocorticoid receptor.

In some embodiments, a reduction in signaling triggered byglucocorticoid receptor activation is used to identify glucocorticoidreceptor modulators. Signaling activity of the glucocorticoid receptorcan be determined in many ways. For example, downstream molecular eventscan be monitored to determine signaling activity. Downstream eventsinclude those activities or manifestations that occur as a result ofstimulation of a glucocorticoid receptor. Exemplary downstream eventsuseful in the functional evaluation of transcriptional activation andantagonism in unaltered cells include upregulation of a number ofglucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosineamino transferase, aromatase). In addition, specific cell typessusceptible to GR activation may be used, such as osteocalcin expressionin osteoblasts which is downregulated by glucocorticoids; primaryhepatocytes which exhibit glucocorticoid mediated upregulation of PEPCKand glucose-6-phosphate (G-6-Pase)). GRE-mediated gene expression hasalso been demonstrated in transfected cell lines using well-knownGRE-regulated sequences (e.g., the mouse mammary tumor virus promoter(MMTV) transfected upstream of a reporter gene construct). Examples ofuseful reporter gene constructs include luciferase (luc), alkalinephosphatase (ALP) and chloramphenicol acetyl transferase (CAT). Thefunctional evaluation of transcriptional repression can be carried outin cell lines such as monocytes or human skin fibroblasts. Usefulfunctional assays include those that measure IL-1beta stimulated IL-6expression; the downregulation of collagenase, cyclooxygenase-2 andvarious chemokines (MCP-1, RANTES); LPS stimulated cytokine release,e.g., TNFα; or expression of genes regulated by NFkB or AP-1transcription factors in transfected cell-lines.

Compounds that are tested in whole-cell assays can also be tested in acytotoxicity assay. Cytotoxicity assays are used to determine the extentto which a perceived effect is due to non-glucocorticoid receptorbinding cellular effects. In an exemplary embodiment, the cytotoxicityassay includes contacting a constitutively active cell with the testcompound. Any decrease in cellular activity indicates a cytotoxiceffect.

3) Additional Assays

Further illustrative of the many assays which can be used to identifycompositions utilized in the methods of the invention, are assays basedon glucocorticoid activities in vivo. For example, assays that assessthe ability of a putative GR modulator to inhibit uptake of 3H-thymidineinto DNA in cells which are stimulated by glucocorticoids can be used.Alternatively, the putative GR modulator can complete with3H-dexamethasone for binding to a hepatoma tissue culture GR (see, e.g.,Choi, et al., Steroids 57:313-318, 1992). As another example, theability of a putative GR modulator to block nuclear binding of3H-dexamethasone-GR complex can be used (Alexandrova et al., J. SteroidBiochem. Mol. Biol. 41:723-725, 1992). To further identify putative GRmodulators, kinetic assays able to discriminate between glucocorticoidagonists and modulators by means of receptor-binding kinetics can alsobe used (as described in Jones, Biochem J. 204:721-729, 1982).

In another illustrative example, the assay described by Daune, Molec.Pharm. 13:948-955, 1977; and in U.S. Pat. No. 4,386,085, can be used toidentify anti-glucocorticoid activity. Briefly, the thymocytes ofadrenalectomized rats are incubated in nutritive medium containingdexamethasone with the test compound (the putative GR modulator) atvarying concentrations. ³H-uridine is added to the cell culture, whichis further incubated, and the extent of incorporation of radiolabel intopolynucleotide is measured. Glucocorticoid agonists decrease the amountof ³H-uridine incorporated. Thus, a GR modulator will oppose thiseffect.

iii. Selectivity

The GR modulators selected above are then subject to a selectivity assayto determine whether they are SGRMs. Typically, selectivity assaysinclude testing a compound that binds glucocorticoid receptor in vitrofor the degree of binding to non-glucocorticoid receptor proteins.Selectivity assays may be performed in vitro or in cell based systems,as described above. Binding may be tested against any appropriatenon-glucocorticoid receptor protein, including antibodies, receptors,enzymes, and the like. In an exemplary embodiment, thenon-glucocorticoid receptor binding protein is a cell-surface receptoror nuclear receptor. In another exemplary embodiment, thenon-glucocorticoid receptor protein is a steroid receptor, such asestrogen receptor, progesterone receptor, androgen receptor, ormineralocorticoid receptor.

The selectivity of the antagonist for the GR relative to the MR can bemeasured using a variety of assays known to those of skill in the art.For example, specific antagonists can be identified by measuring theability of the antagonist to bind to the GR compared to the MR (see,e.g., U.S. Pat. Nos. 5,606,021; 5,696,127; 5,215,916; 5,071,773). Suchan analysis can be performed using either a direct binding assay or byassessing competitive binding to the purified GR or MR in the presenceof a known ligand. In an exemplary assay, cells that stably express theglucocorticoid receptor or mineralocorticoid receptor (see, e.g., U.S.Pat. No. 5,606,021) at high levels are used as a source of purifiedreceptor. The affinity of the ligandfor the receptor is then directlymeasured. Those GR modulators that exhibit at least a 10 fold, 100-foldhigher affinity, often 1000-fold, for the GR relative to the MR are thenselected for use in the methods of the invention.

The selectivity assay may also include assaying the ability to inhibitGR-mediated activities, but not MR-mediated activities. One method ofidentifying such a GR-specific modulator is to assess the ability of anantagonist to prevent activation of reporter constructs usingtransfection assays (see, e.g., Bocquel et al, J. Steroid Biochem Molec.Biol. 45:205-215, 1993; U.S. Pat. Nos. 5,606,021, 5,929,058). In anexemplary transfection assay, an expression plasmid encoding thereceptor and a reporter plasmid containing a reporter gene linked toreceptor-specific regulatory elements are cotransfected into suitablereceptor-negative host cells. The transfected host cells are thencultured in the presence and absence of a hormone, such as cortisol oran analog thereof, able to activate the hormone responsivepromoter/enhancer element of the reporter plasmid. Next the transfectedand cultured host cells are monitored for induction (i.e., the presence)of the product of the reporter gene sequence. Finally, the expressionand/or steroid binding-capacity of the hormone receptor protein (codedfor by the receptor DNA sequence on the expression plasmid and producedin the transfected and cultured host cells), is measured by determiningthe activity of the reporter gene in the presence and absence of anantagonist. The antagonist activity of a compound may be determined incomparison to known antagonists of the GR and MR receptors (see, e.g.,U.S. Pat. No. 5,696,127). Efficacy is then reported as the percentmaximal response observed for each compound relative to a referenceantagonist compound. GR modulators that exhibits at least a 100-fold,often 1000-fold or greater, activity towards the GR relative to the MR,PR, or AR are then selected for use in the methods disclosed herein.

An exemplar nonsteroidal SGRM that can be used in the methods disclosedherein is CORT 125134, i.e.,(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

Another exemplar nonsteroidal SGRM that can be used in the methodsdisclosed herein is CORT125281, i.e.,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

G. Pharmaceutical Compositions and Administration

In embodiments, the present invention provides a pharmaceuticalcomposition for treating non-ACTH-secreting pancreatic tumors, thepharmaceutical composition including a pharmaceutically acceptableexcipient and a GRM. In some embodiments, the pharmaceutical compositionincludes a pharmaceutically acceptable excipient and a SGRM. Inpreferred embodiments, the pharmaceutical composition includes apharmaceutically acceptable excipient and a nonsterodial SGRM.

GRMs and SGRMs (as used herein, GRMs and SGRMs include nonsteroidal GRMsand nonsteroidal SGRMS), can be prepared and administered in a widevariety of oral, parenteral and topical dosage forms. Oral preparationsinclude tablets, pills, powder, dragees, capsules, liquids, lozenges,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. GRMs and SGRMs can also be administered by injection, that is,intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally. Also, GRMs and SGRMs can beadministered by inhalation, for example, intranasally. Additionally,GRMs and SGRMs can be administered transdermally. Accordingly, thepresent invention also provides pharmaceutical compositions including apharmaceutically acceptable carrier or excipient and a GRM or SGRM.

For preparing pharmaceutical compositions from GRMs and SGRMs,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances, which may also act as diluents, flavoringagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. Details on techniques for formulation andadministration are well described in the scientific and patentliterature, see, e.g., the latest edition of Remington's PharmaceuticalSciences, Maack Publishing Co, Easton Pa. (“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component, a GRM or SGRM. In tablets, theactive component is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

Suitable solid excipients are carbohydrate or protein fillers include,but are not limited to sugars, including lactose, sucrose, mannitol, orsorbitol; starch from corn, wheat, rice, potato, or other plants;cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain GRmodulator mixed with a filler or binders such as lactose or starches,lubricants such as talc or magnesium stearate, and, optionally,stabilizers. In soft capsules, the GR modulator compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycol with or without stabilizers.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending a SGRM in a vegetableoil, such as arachis oil, olive oil, sesame oil or coconut oil, or in amineral oil such as liquid paraffin; or a mixture of these. The oilsuspensions can contain a thickening agent, such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents can be added to provide apalatable oral preparation, such as glycerol, sorbitol or sucrose. Theseformulations can be preserved by the addition of an antioxidant such asascorbic acid. As an example of an injectable oil vehicle, see Minto, J.Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulationsof the invention can also be in the form of oil-in-water emulsions. Theoily phase can be a vegetable oil or a mineral oil, described above, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

GRMs and SGRMs can be delivered by transdermally, by a topical route,formulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

GRMs and SGRMs can also be delivered as microspheres for slow release inthe body. For example, microspheres can be administered via intradermalinjection of drug-containing microspheres, which slowly releasesubcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; asbiodegradable and injectable gel formulations (see, e.g., Gao Pharm.Res. 12:857-863, 1995); or, as microspheres for oral administration(see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Bothtransdermal and intradermal routes afford constant delivery for weeks ormonths.

The pharmaceutical formulations of the invention can be provided as asalt and can be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thatare the corresponding free base forms. In other cases, the preparationmay be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose,2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with bufferprior to use

In another embodiment, the formulations of the invention can bedelivered by the use of liposomes which fuse with the cellular membraneor are endocytosed, i.e., by employing ligands attached to the liposome,or attached directly to the oligonucleotide, that bind to surfacemembrane protein receptors of the cell resulting in endocytosis. Byusing liposomes, particularly where the liposome surface carries ligandsspecific for target cells, or are otherwise preferentially directed to aspecific organ, one can focus the delivery of the GR modulator into thetarget cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro,Am. J. Hosp. Pharm. 46:1576-1587, 1989).

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component, a GRM or SGRM. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to6000 mg, most typically 50 mg to 500 mg. Suitable dosages also includeabout 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400,500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900, or 2000 mg, according to the particular application and thepotency of the active component. The composition can, if desired, alsocontain other compatible therapeutic agents.

Single or multiple administrations of formulations can be administereddepending on the dosage and frequency as required and tolerated by thepatient. The formulations should provide a sufficient quantity of activeagent to effectively treat the disease state. Thus, in one embodiment,the pharmaceutical formulation for oral administration of a GRM is in adaily amount of between about 0.01 to about 150 mg per kilogram of bodyweight per day (mg/kg/day). In some embodiments, the daily amount isfrom about 1.0 to 100 mg/kg/day, 5 to 50 mg/kg/day, 10 to 30 mg/kg/day,and 10 to 20 mg/kg/day. Lower dosages can be used, particularly when thedrug is administered to an anatomically secluded site, such as thecerebral spinal fluid (CSF) space, in contrast to administration orally,into the blood stream, into a body cavity or into a lumen of an organ.Substantially higher dosages can be used in topical administration.Actual methods for preparing parenterally administrable formulationswill be known or apparent to those skilled in the art and are describedin more detail in such publications as Remington's, supra. See alsoNieman, In “Receptor Mediated Antisteroid Action,” Agarwal, et al.,eds., De Gruyter, New York (1987).

The duration of treatment with a GRM or SGRM to reduce the tumor load ofnon-ACTH-secreting pancreatic tumor or otherwise ameliorate the symptomsof the tumor can vary according to the severity of the condition in asubject and the subject's response to GRMs or SGRMs. In someembodiments, GRMs and SGRMs can be administered for a period of about 1week to 104 weeks (2 years), more typically about 6 weeks to 80 weeks,most typically about 9 to 60 weeks. Suitable periods of administrationalso include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks,16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64 weeks, 52 to 72 weeks,64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitableperiods of administration also include 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48 50, 52, 55,60, 64, 65, 68, 70, 72, 75, 80, 85, 88 90, 95, 96, 100, and 104 weeks.Generally administration of a GRM or SGRM should be continued untilclinically significant reduction or amelioration is observed. Treatmentwith the GRM or SGRM in accordance with the invention may last for aslong as two years or even longer.

In some embodiments, administration of a GRM or SGRM is not continuousand can be stopped for one or more periods of time, followed by one ormore periods of time where administration resumes. Suitable periodswhere administration stops include 5 to 9 weeks, 5 to 16 weeks, 9 to 16weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks,32 to 48 weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks,72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96to 100 weeks. Suitable periods where administration stops also include5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30,32, 35, 40, 45, 48 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 8890, 95, 96, and 100 weeks.

The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the rate of absorption,bioavailability, metabolism, clearance, and the like (see, e.g.,Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617;Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995)Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108;the latest Remington's, supra). The state of the art allows theclinician to determine the dosage regimen for each individual patient,GR modulator and disease or condition treated.

SGRMs can be used in combination with other active agents known to beuseful in modulating a glucocorticoid receptor, or with adjunctiveagents that may not be effective alone, but may contribute to theefficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent, a GRM or SGRM, within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24hours of a second active agent. Co-administration includes administeringtwo active agents simultaneously, approximately simultaneously (e.g.,within about 1, 5, 10, 15, 20, or 30 minutes of each other), orsequentially in any order. In some embodiments, co-administration can beaccomplished by co-formulation, i.e., preparing a single pharmaceuticalcomposition including both active agents. In other embodiments, theactive agents can be formulated separately. In another embodiment, theactive and/or adjunctive agents may be linked or conjugated to oneanother.

After a pharmaceutical composition including a GR modulator of theinvention has been formulated in an acceptable carrier, it can be placedin an appropriate container and labeled for treatment of an indicatedcondition. For administration of a GRM or SGRM, such labeling wouldinclude, e.g., instructions concerning the amount, frequency and methodof administration.

The pharmaceutical compositions of the present invention can be providedas a salt and can be formed with many acids, including but not limitedto hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic,etc. Salts tend to be more soluble in aqueous or other protonic solventsthat are the corresponding free base forms. In other cases, thepreparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2%sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combinedwith buffer prior to use.

In another embodiment, the compositions of the present invention areuseful for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

H. Chemotherapeutic Agents

Chemotherapeutic agents suitable for use in combination with the SGRM ofthe invention include agents that have the property of killing cancercells or inhibiting cancer cell growth, such as those disclosed in USPat. Pub. No. 20150218274, and alsohttp://chemocare.com/chemotherapy/what-is-chemotherapy/types-of-chemotherapy.aspx.These agents include, but are not limited to antimicrotubule agents(e.g., taxanes and vinca alkaloids), topoisomerase inhibitors andantimetabolites (e.g., nucleoside analogs acting as such, for example,Gemcitabine), mitotic inhibitors, alkylating agents, antimetabolites,anti-tumor antibiotics, mitotic inhibitors, anthracyclines,intercalating agents, agents capable of interfering with a signaltransduction pathway, agents that promote apoptosis, proteosomeinhibitors, and the like.

Alkylating agents are most active in the resting phase of the cell.These types of drugs are cell-cycle non-specific. Exemplary alkylatingagents that can be used in combination with the SGRM of the inventioninclude, without limitation, nitrogen mustards, ethyleniminederivatives, alkyl sulfonates, nitrosoureas and triazenes): uracilmustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®,Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®,Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine(Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®,Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®),Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®),triethylenemelamine (Hemel®, Hexalen®, Hexastat®),triethylenethiophosphoramine, thiotepa (Thioplex®), busulfan (Busilvex®,Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin(Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplaryalkylating agents include, without limitation, Oxaliplatin (Eloxatin®);Temozolomide (Temodar® and Temodal®); Dactinomycin (also known asactinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-sarcolysin,and phenylalanine mustard, Alkeran®); Altretamine (also known ashexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine(Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin(Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (alsoknown as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®);Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known asDTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (alsoknown as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®);Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known asnitrogen mustard, mustine and mechloroethamine hydrochloride,Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known asthiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide(Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and BendamustineHCl (Treanda®).

Antitumor antibiotics are chemo agents obtained from natural productsproduced by species of the soil fungus Streptomyces. These drugs actduring multiple phases of the cell cycle and are considered cell-cyclespecific. There are several types of antitumor antibiotics, includingbut are not limited to Anthracyclines (e.g., Doxorubicin, Daunorubicin,Epirubicin, Mitoxantrone, and Idarubicin), Chromomycins (e.g.,Dactinomycin and Plicamycin), Mitomycin and Bleomycin.

Antimetabolites are types of chemotherapy treatments that are cell-cyclespecific. When the cells incorporate these antimetabolite substancesinto the cellular metabolism, they are unable to divide. These class ofchemotherapy agents include folic acid antagonists such as Methotrexate;pyrimidine antagonists such as 5-Fluorouracil, Foxuridine, Cytarabine,Capecitabine, and Gemcitabine; purine antagonists such as6-Mercaptopurine and 6-Thioguanine; Adenosine deaminase inhibitors suchas Cladribine, Fludarabine, Nelarabine and Pentostatin.

Exemplary anthracyclines that can be used in combination with the SGRMof the invention include, e.g., doxorubicin (Adriamycin® and Rubex®);Bleomycin (Lenoxane®); Daunorubicin (dauorubicin hydrochloride,daunomycin, and rubidomycin hydrochloride, Cerubidine®); Daunorubicinliposomal (daunorubicin citrate liposome, DaunoXome®); Mitoxantrone(DHAD, Novantrone®); Epirubicin (Ellence); Idarubicin (Idamycin®,Idamycin PFS®); Mitomycin C (Mutamycin®); Geldanamycin; Herbimycin;Ravidomycin; and Desacetylravidomycin.

Antimicrotubule agents include vinca alkaloids and taxanes. Exemplaryvinca alkaloids that can be used in combination with the SGRM of theinvention include, but are not limited to, vinorelbine tartrate(Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®));vinblastine (also known as vinblastine sulfate, vincaleukoblastine andVLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®). Exemplarytaxanes that can be used in combination with the SGRM of the inventioninclude, but are not limited to paclitaxel and docetaxel. Non-limitingexamples of paclitaxel agents include nanoparticle albumin-boundpaclitaxel (ABRAXANE, marketed by Abraxis Bioscience), docosahexaenoicacid bound-paclitaxel (DHA-paclitaxel, Taxoprexin, marketed byProtarga), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxelpoliglumex, CT-2103, XYOTAX, marketed by Cell Therapeutic), thetumor-activated prodrug (TAP), ANG105 (Angiopep-2 bound to threemolecules of paclitaxel, marketed by ImmunoGen), paclitaxel-EC-1(paclitaxel bound to the erbB2-recognizing peptide EC-1; see Li et al.,Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g.,2′-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al.,Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620).

Exemplary proteosome inhibitors that can be used in combination with theSGRM of the invention, include, but are not limited to, Bortezomib(Velcade®); Carfilzomib (PX-171-007,(S)-4-Methyl-N—((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-pentanamide);marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib(CEP-18770); andO-Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(-2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide(ONX-0912).

In some embodiments, the chemotherapeutic agent is selected from thegroup consisting of chlorambucil, cyclophosphamide, ifosfamide,melphalan, streptozocin, carmustine, lomustine, bendamustine,uramustine, estramustine, carmustine, nimustine, ranimustine,mannosulfan busulfan, dacarbazine, temozolomide, thiotepa, altretamine,5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine,cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea,methotrexate, pemetrexed, daunorubicin, doxorubicin, epirubicin,idarubicin, SN-38, ARC, NPC, campothecin, topotecan,9-nitrocamptothecin, 9-aminocamptothecin, rubifen, gimatecan,diflomotecan, BN80927, DX-895 If, MAG-CPT, amsacrine, etoposide,etoposide phosphate, teniposide, doxorubicin, paclitaxel, docetaxel,gemcitabine, accatin III, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol,cephalomannine, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatinIII, 10-deacetyl cephalomannine, gemcitabine, Irinotecan, albumin-boundpaclitaxel, Oxaliplatin, Capecitabine, Cisplatin, docetaxel, irinotecanliposome, and etoposide, and combinations thereof.

In certain embodiments, the chemotherapeutic agent is administered at adose and a schedule that may be guided by doses and schedules approvedby the U.S. Food and Drug Administration (FDA) or other regulatory body,subject to empirical optimization. In some cases, the chemotherapeuticagent is administered at a dose of about 100 to 1000 mg, e.g., about 200mg to 800 mg, about 300 mg to 700 mg, or about 400 mg to 600 mg, e.g.,about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg. The dosingschedule can vary from, e.g. every week, every five days, every fourdays, every other day to daily, twice, or three times a day. In oneembodiment, the chemotherapeutic agent is administered at an oral doseor an intravenous dose from about 100 mg to 600 mg daily, e.g., about100 mg, 200 mg, 260 mg, 300 mg, 400 mg, or 600 mg daily, every other dayor every four days for the whole or a portion of the treatment period.In some embodiments, the chemotherapeutic agent is a taxane and can beused at any standard dose, for example those taxane doses approved bythe FDA, in accordance with the methods of the invention. In variousembodiments, the taxane is nab-paclitaxel, which is administered at adose ranging from 80 mg to 125 mg per square meter of body-surface areaas an intravenous infusion over 30 minutes on days 1, 8, and 15 of every28-day cycle.

In still further embodiments, more than one chemotherapeutic agent maybe administered simultaneously, or sequentially in any order during theentire or portions of the treatment period. The two agents may beadministered following the same or different dosing regimens.

I. Combination Therapies

Various combinations with a GRM or SGRM and a chemotherapeutic agent (ora combination of such agents and compounds) may be employed to reducethe tumor load in the patient. By “combination therapy” or “incombination with”, it is not intended to imply that the therapeuticagents must be administered at the same time and/or formulated fordelivery together, although these methods of delivery are within thescope described herein. The GRM or SGRM and the chemotherapeutic agentcan be administered following the same or different dosing regimen. Insome embodiments, the GRM or SGRM and the chemotherapeutic agent isadministered sequentially in any order during the entire or portions ofthe treatment period. In some embodiments, the GRM or SGRM and theanticancer agent is administered simultaneously or approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other). Non-limiting examples of combination therapies are asfollows, with administration of the GRM or SGRM and the chemo agent forexample, GRM or SGRM is “A” and the anticancer agent or compound, givenas part of an chemo therapy regime, is “B”:

A/B/AB/A/BB/B/AA/A/BA/B/BB/A/AA/B/B/B B/A/B/B B/B/B/A B/B/A/B A/A/B/BA/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

Administration of the therapeutic compounds or agents to a patient willfollow general protocols for the administration of such compounds,taking into account the toxicity, if any, of the therapy. Surgicalintervention may also be applied in combination with the descirbedtherapy.

The present methods involvincan be combined with other means oftreatment such as surgery, radiation, targeted therapy, immunotherapy,use of growth factor inhibitors, or anti-angiogenesis factors.

J. Evaluate Improvements in Reducing Tumor Loads

The GRM or SGRM therapy disclosed herein can reduce the tumor load andconfer beneficial clinical outcome to patients having anon-ACTH-secreting pancreatic tumor. Methods for measuring theseresponses are well-known to skilled artisans in the field of cancertherapy, e.g., as described in the Response Evaluation Criteria in SolidTumors (“RECIST”) guidelines, available atctep.cancer.gov/protocolDevelopment/docs/recist guideline.pdf.

In one approach, the tumor load is measured by assaying expression oftumor-specific biomarkers. This approach is especially useful formetastatic tumors. A tumor-specific biomarker is a protein or othermolecule that is unique to cancer cells or is much more abundant in themas compared to non-cancer cells. Useful biomarkers for pancreatic cancerare known, for example, CaSM gene, as disclosed in U.S. Pat. No.6,720,413, and p53, MUC1, Rad51, DEAD-box protein 48, Calreticulin,Vimentin, Osteopontin, etc. as disclosed in Misek et al., J. Natl.Compr. Canc. Netw. 2007; 5(10): 1034-1041. In some cases, the level ofCA19-9, which are foreign substances released by pancreatic tumor cells,is evaluted throughout the treatment—decreasing in CA 19-9 values mayindicate that treatment is effective and that the tumor or amount ofcancer in the body is decreasing. A decline in CA 19-9 levels aftertreatment for pancreatic cancer followed by a rise later may suggesttumor recurrence or progression. See,https://www.pancan.org/facing-pancreatic-cancer/diagnosis/CA19-9.

Methods of measuring the expression levels of a tumor-specific geneticmarker are well known. In some embodiments, mRNA of the genentic markeris isolated from the blood sample or a tumor tissue and real-timereverse transcriptase-polymerase chain reaction (RT-PCR) is performed toquantify expression of the genetic marker. In some embodiments, westernblots or immunohistochemistry analysis are performed to evaluate theprotein expression of the tumor-specific genetic marker. Typically thelevels of the tumor-specific genetic marker are measured in multiplesamples taken over time of the combination therapy of the invention, anda decrease in levels correlates with a reduction in tumor load.

In another approach, the reduction of tumor load by the combinationtherapy disclosed herein is shown by a reduction in tumor size or areduction of amount of cancer in the body. Measuring tumor size istypically achieved by imaging-based techniques. For example, computedtomography (CT) scan can provide accurate and reliable anatomicinformation about not only tumor shrinkage or growth but alsoprogression of disease by identifying either growth in existing lesionsor the development of new lesions or tumor metastasis.

In yet another approach, a reduction of tumor load can be assessed byfunctional and metabolic imaging techniques. These techniques canprovide earlier assessment of therapy response by observing alterationsin perfusion, oxygenation and metabolism. For example, ¹⁸F-FDG PET usesradiolabelled glucose analogue molecules to assess tissue metabolism.Tumors typically have an elevated uptake of glucose, a change in valuecorresponding to a decrease in tumor tissue metabolism indicates areduction in tumor load. Similar imaging techniques are disclosed inKang et al., Korean J. Radiol. (2012) 13(4) 371-390.

A patient receiving the therapy disclosed herein may exhibit varyingdegrees of tumor load reduction. In some cases, a patient can exhibit aComplete Response (CR), also referred to as “no evidence of disease(NED)”. CR means all detectable tumor has disappeared as indicated bytests, physical exams and scans. In some cases, a patient receiving thecombination therapy disclosed herein can experience a Partial Response(PR), which roughly corresponds to at least a 50% decrease in the totaltumor volume but with evidence of some residual disease still remaining.In some cases the residual disease in a deep partial response mayactually be dead tumor or scar so that a few patients classified ashaving a PR may actually have a CR. Also many patients who showshrinkage during treatment show further shrinkage with continuedtreatment and may achieve a CR. In some cases, a patient receiving thecombination therapy can experience a Minor Response (MR), which roughtlymeans a small amount of shrinkage that is more than 25% of total tumorvolume but less than the 50% that would make it a PR. In some cases, apatient receiving the combination therapy can exhibit Stable Disease(SD), which means the tumors stay roughly the same size, but can includeeither a small amount of growth (typically less than 20 or 25%) or asmall amount of shrinkage (Anything less than a PR unless minorresponses are broken out. If so, then SD is defined as typically less25%).

Desired beneficial or desired clinical results from the combinationtherapy may also include e. g., reduced (i.e., slowing to some extentand/or stop) cancer cell infiltration into peripheral organs; inhibited(i.e., slowing to some extent and/or stop) tumor metastasis; increasedresponse rates (RR); increased duration of response; relieved to someextent one or more of the symptoms associated with the cancer; decreaseddose of other medications required to treat the disease; delayedprogression of the disease; and/or prolonged survival of patients and/orimproved quality of life. Methods for evaluating these effects are wellknown and/or disclosed in, e.g., cancerguide.org/endpoints.html andRECIST guidelines, supra.

All patents, patent publications, publications, and patent applicationscited in this specification are hereby incorporated by reference hereinin their entireties as if each individual publication or patentapplication were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

EXAMPLES

The following examples are provided by way of illustration only and notby way of limitation. Those of skill will readily recognize a variety ofnoncritical parameters which could be changed or modified to yieldessentially similar results.

Example 1. HEPG2 Tyrosine Aminotransferase (TAT) Assay

The following protocol describes an assay for measuring induction of TATby dexamethasone in HepG2 cells (a human liver hepatocellular carcinomacell line; ECACC, UK). HepG2 cells are cultured using MEME mediasupplemented with 10% (v/v) foetal bovine serum; 2 mM L-glutamine and 1%(v/v) NEAA at 37° C., 5%/95% (v/v) CO₂/air. The HepG2 cells are then becounted and adjusted to yield a density of 0.125×10⁶ cells/ml in RPMI1640 without phenol red, 10% (v/v) charcoal stripped FBS, 2 mML-glutamine and seeded at 25,000 cells/well in 200 μl into 96 well,sterile, tissue culture micro titre plates, and incubated at 37° C., 5%CO₂ for 24 hours.

Growth media are then removed and replaced with assay media {RPMI 1640without phenol red, 2 mM L-glutamine+10 μM forskolin}. Test compoundsare then screened against a challenge of 100 nM dexamethasone. Compoundsare then be serially half log diluted in 100% (v/v) dimethylsupfoxidefrom a 10 mM stock. Then an 8-point half-log dilution curve aregenerated followed by a 1:100 dilution into assay media to give a 10×final assay of the compound concentration, this results in final assayof the compound concentration that ranged 10 to 0.003 μM in 0.1% (v/v)dimethylsulfoxide.

Test compounds are pre-incubated with cells in micro-titre plates for 30minutes at 37° C., 5/95 (v/v) CO₂/air, before the addition of 100 nMdexamethasone and then subsequently for 20 hours to allow optimal TATinduction.

HepG2 cells are then lysed with 30 μl of cell lysis buffer containing aprotease inhibitor cocktail for 15 minutes at 4° C. 155 μl of substratemixture can then be added containing 5.4 mM Tyrosine sodium salt, 10.8mM alpha ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1Mpotassium phosphate buffer (pH 7.4). After 2 hours incubation at 37° C.the reaction can be terminated by the addition of 15 μl of 10M aqueouspotassium hydroxide solution, and the plates incubated for a further 30minutes at 37° C. The TAT activity product can be measured by absorbanceat λ 340 nm.

IC₅₀ values can be calculated by plotting % inhibition (normalised to100 nM dexamethasone TAT stimulation) v. compound concentration andfitting the data to a 4 parameter logistic equation. IC₅₀ values canconverted to Ki (equilibrium dissociation constant) using the Cheng andPrusoff equation, assuming the antagonists were competitive inhibitorswith respect to dexamethasone.

Example 2. Reducing Tumor Growth Using the Combination Therapy of CORT125134 and a Chemotherapeutic Agent

Human Pancreatic carcinoma cells (MIA-PaCa-2) were purchased from theAmerican Type Cell Collection (ATCC). The cells were grown in Dulbecco'sModified Eagle's Medium (DMEM) containing 10% (v/v) heat inactivatedfetal calf serum and 2.5% horse serum at 37° C. Suspensions of the cellswere injected subcutaneously into the left flank of 5-6 week oldimmunocompromised female mice (Balbc/c nude), 3 million cells per mouse.Tumors were allowed to grow until they reach a volume of 100-200 cubicmillimeters (mm³). Mice were then grouped into four groups, ten (10) pergroup, and treated with compounds or vehicle as follows. Vehicle orpaclitaxel was administered intravenously and SGRMs, i.e., CORT25134 andCORT125281, were administered orally. SGRMs were administered in vehicle((10% dimethyl sulfoxide (DMSO), 0.1% Tween 80 (polyethylene glycolsorbitan monooleate (polysorbate 80)) and 89.9% hydroxypropylmethylcellulose (HPMC) (0.5%)). Group 1 was dosed with the compoundvehicle (10% DMSO, 0.1% Tween 80 and 89.9% HPMC (0.5%)) daily. Group 2was dosed with paclitaxel at 7.5 mg/kg, every four days (“Q4D”). Group 3was dosed with both paclitaxel at 7.5 mg/kg Q4D and CORT125134 at 30mg/kg on the day prior to and the same day as the day paclitaxel wasadministered. Group 4 was dosed with both paclitaxel at 7.5 mg/kg Q4Dand CORT125281 at 30 mg/kg on the day prior to and the same day as theday paclitaxel was administered.

The longest (L) and shortest (S) diameters of the tumors were measuredthree times a week with electronic calipers and tumor volume wascalculated using the formula V=0.5 a×b², where a and b are the long andshort diameters of the tumor, respectively. The tumor growth data areshown in The FIGURE, in which the mean tumor volume as compared to themean pre-dosing tumor volume for each group of mice is plotted againstthe number of days of tumor growth since initiation of the treatment.The result shows that the combination of paclitaxel and SGRM, i.e.,CORT125134 or CORT125281, are superior to the paclitaxel group inreducing tumor growth. Mice treated with the combination of thepaclitaxel and CORT125134 showed the most significant tumor growthreduction.

Example 3. Treating a Patient Having Pancreatic Cancer with Sgrm and aChemotherapeutic Agent

A typical pancreatic patient may complain of upper abdomen pain thattypically radiates to the back. Such a patient may experience loss ofappetite, nausea and vomiting episodes, and may suffer significantweight loss. A CT scan may show the presence of a tumor in the pancreas.The presence of an exocrine pancreatic tumor may be confirmed byhistological analysis. Blood ACTH level may be within the normal rangefor ACTH. Such a patient may be treated with CORT125134 at a dose of 200mg once a day for eight weeks in combination with an intravenousinfusion of nab-paclitaxel at a dose of 80 mg per square meter ofbody-surface area as an intravenous infusion over 30 minutes on days 1,8, and 15 of every 28-day cycle. Tumor load may be monitored usingenhanced Mill before, during and after such treatment. Imaging resultsmay indicate that the size of the tumor gradually decreases; suchreduction may be more than 50% at the end of the treatment period.

Example 4. Treatment of a Patient Having Advanced Pancreatic Cancer withSGRM and a Chemotherapeutic Agent Following Tumor Progression onMultiple Prior Chemotherapeutic Treatments

A 39-year-old patient with a diagnosis of metastatic adenocarcinoma ofthe pancreas participated in a clinical study evaluating the efficacy ofdaily administration of 100 mg of the GR antagonist CORT125134 incombination with nab-paclitaxel infusions weekly for three out of fourweeks per cycle. A tumor tissue sample obtained during or prior to thepatient's previous treatments was found by immunohistochemistry to havehigh GR expression, with 90 percent of the cells staining for GR andwith a large percentage staining with high intensity. Prior to receivingthis combined GR antagonist and nab-paclitaxel treatment, the patienthad previously received treatment with multiple lines of chemotherapy:gemcitabine monotherapy; eight months of combination chemotherapytreatment with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin(FOLFIRINOX treatment); five months of treatment with gemcitabinecombined with nab-paclitaxel; and four months of combinationchemotherapy treatment with 5-fluorouracil, leuvocorin, and irinotecanhydrochloride (FOLFIRI treatment). These prior treatments wereunsuccessful: the patient's cancer progressed despite these priorchemotherapy treatments.

This patient has so far received 8 months (8 cycles) of the combinedtreatment of daily 100 mg CORT125134 in combination with nab-paclitaxelinfusions weekly for three out of four weeks per cycle. The patient hasexperienced a partial response (PR) to this treatment by the combinationof CORT125134 and nab-paclitaxel, and has tolerated the treatmentreasonably well. On the third month/cycle of treatment, the tumor volumewas observed to be reduced by approximately 40% as compared to the tumorvolume measured at the start of the study (volume measurements were madeusing computer tomography (CT) scans). When scanned again one monthlater, the tumor volume was still reduced by approximately 40% comparedto baseline volume, thus confirming the PR status. A further scan duringthe seventh month of treatment was also performed, and the patient wasfound to have retained the 40% reduction (compared to baseline) in tumorvolume. The patient remains on the treatment, and continues to toleratethe treatment well.

In summary, this patient with advanced pancreatic cancer has exhibitedan excellent clinical response by achieving a sustained partial responseduring 8 months of the treatment. The patient has tolerated thetreatment with CORT125134 and nab-paclitaxel well, and continues toreceive further cycles of the treatment. It is notable that this patienthad previously experienced significant growth/progression of her tumorduring prior chemotherapies, which included treatment withnab-paclitaxel and gemcitabine in combination. Thus, the combination ofCORT125134 daily 100 mg with nab-paclitaxel infusions weekly for threeout of four weeks per cycle in the treatment of advanced pancreaticcancer in this patient produced regression in tumor volume and provideda more durable response than had treatment with nab-paclitaxel plusgemcitabine.

What is claimed is:
 1. A method of treating a subject hosting anon-ACTH-secreting pancreatic tumor, the method comprising administeringto the subject an effective amount of a chemotherapeutic agent and aneffective amount of a nonsteroidal selective glucocorticoid receptormodulator to reduce the tumor load of the pancreatic tumor, wherein thenonsteroidal selective glucocorticoid receptor modulator is a compoundcomprising a fused azadecalin structure having the formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.
 2. The method of claim 1, wherein thenon-ACTH-secreting pancreatic tumor is an exocrine pancreatic tumor. 3.The method of claim 1, wherein the chemotherapeutic agent is selectedfrom the group consisting of taxanes, alkylating agents, topoisomeraseinhibitors, endoplasmic reticulum stress inducing agents,antimetabolites, mitotic inhibitors and combinations thereof.
 4. Themethod of claim 3, wherein the chemotherapeutic agent is a taxane. 5.The method of claim 3, wherein the chemotherapeutic agent is selectedfrom the group consisting of nab-paclitaxel, 5-fluorouracil (5-FU),gemcitabine, cisplatin and capecitabine.
 6. The method of claim 1,wherein the nonsteroidal selective glucocorticoid receptor modulatorcompound is the compound comprising a fused azadecalin structure havingthe formula:


7. A method of treating a subject hosting a non-ACTH-secretingpancreatic tumor, the method comprising administering to the subject aneffective amount of a chemotherapeutic agent and an effective amount ofa nonsteroidal selective glucocorticoid receptor modulator to reduce thetumor load of the pancreatic tumor, wherein the nonsteroidal selectiveglucocorticoid receptor modulator is a compound comprising a heteroarylketone fused azadecalin structure having the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₆ haloalkyl, C₁ ₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, CN,OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b), SR^(2a),S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl groups are optionally substituted with 1-4R^(2c) groups; alternatively, two R² groups linked to the same carbonare combined to form an oxo group (═O); alternatively, two R² groups arecombined to form a heterocycloalkyl ring having from 5 to 6 ring membersand from 1 to 3 heteroatoms each independently selected from the groupconsisting of N, O and S, wherein the heterocycloalkyl ring isoptionally substituted with from 1 to 3 R^(2d) groups; R^(2a) and R^(2b)are each independently selected from the group consisting of hydrogenand C₁₋₆ alkyl; each R^(2c) is independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,CN, and NR^(2a)R^(2b); each R^(2d) is independently selected from thegroup consisting of hydrogen and C₁₋₆ alkyl, or two R^(2d) groupsattached to the same ring atom are combined to form (═O); R³ is selectedfrom the group consisting of phenyl and pyridyl, each optionallysubstituted with 1-4 R^(3a) groups; each R^(3a) is independentlyselected from the group consisting of hydrogen, halogen, and C₁₋₆haloalkyl; and subscript n is an integer from 0 to 3; or salts andisomers thereof.
 8. The method of claim 7, wherein the nonsteroidalselective glucocorticoid receptor modulator is the compound comprising aheteroaryl ketone fused azadecalin having the formula:


9. A method of treating a subject hosting a non-ACTH-secretingpancreatic tumor, the method comprising administering to the subject aneffective amount of a chemotherapeutic agent and an effective amount ofa nonsteroidal selective glucocorticoid receptor modulator to reduce thetumor load of the pancreatic tumor, wherein the nonsteroidal selectiveglucocorticoid receptor modulator is a compound comprising an octahydrofused azadecalin structure having the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.
 10. The method ofclaim 9, wherein the nonsteroidal selective glucocorticoid receptormodulator is the compound comprising an octahydro fused azadecalinhaving the formula:


11. The method of claim 7, wherein the non-ACTH-secreting pancreatictumor is an exocrine pancreatic tumor.
 12. The method of claim 7,wherein the chemotherapeutic agent is selected from the group consistingof taxanes, alkylating agents, topoisomerase inhibitors, endoplasmicreticulum stress inducing agents, antimetabolites, mitotic inhibitorsand combinations thereof.
 13. The method of claim 12, wherein thechemotherapeutic agent is a taxane.
 14. The method of claim 12, whereinthe chemotherapeutic agent is selected from the group consisting ofnab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin andcapecitabine.
 15. The method of claim 9, wherein the non-ACTH-secretingpancreatic tumor is an exocrine pancreatic tumor.
 16. The method ofclaim 9, wherein the chemotherapeutic agent is selected from the groupconsisting of taxanes, alkylating agents, topoisomerase inhibitors,endoplasmic reticulum stress inducing agents, antimetabolites, mitoticinhibitors and combinations thereof.
 17. The method of claim 16, whereinthe chemotherapeutic agent is a taxane.
 18. The method of claim 16,wherein the chemotherapeutic agent is selected from the group consistingof nab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin andcapecitabine.